Compounds with growth hormone releasing properties

Abstract

Novel peptide derivatives, compositions containing them, and their use for treating medical disorders resulting from a deficiency in growth hormone are disclosed. The peptides have the formula (I): wherein a, b, A, R1, L1, D, R3, R4, R2, L2, E and G are as defined in the specification. These peptides exhibit improved resistance to proteolytic degradation, and hence, improved bioavailability.

What is claimed is: 
     
       1. A compound of formula I ##STR200## wherein A is A 2  ; G is G 2  ;   D is ##STR201##  wherein R 5 , R 6 , R 7 , R 8 , and R 9  independently are hydrogen, halogen, aryl, C 1-6  -alkyl or C 1-6  -alkoxy;   E is ##STR202##  wherein R 10  and R 11  independently are hydrogen, halogen, aryl, C 1-6  -alkyl, C 1-6  -alkoxy, --CONR 15  R 16 , --(CH 2 ) v  --NR 15  SO 2  R 17 , --(CH 2 ) v  --NR 15  COR 16 , --(CH 2 ) v  --OR 17 , --(CH 2 ) v  --OCOR 16 , --CH(R 15 )R 16 , --(CH 2 ) v  --NR 15  --CS--NR 16  R 18  or --(CH 2 ) v  --NR 15  --CO--NR 16  R 18 , wherein     R 15 , or R 16 , independently are hydrogen or C 1-6  -alkyl optionally substituted with halogen, --N(R 26 )R 27 , hydroxyl, C 1-6  -alkoxy, C 1-6  -alkoxycarbonyl, C 1-6  -alkyl-carbonyloxy or aryl,   R 17  is C 1-6  alkyl or phenyl optionally substituted with hydroxyl or aryl;   R 18  is C 1-6  alkyl;   R 26  and R 27  are independently hydrogen or C 1-6  -alkyl;   v and w are independently 0, 1, 2 or 3;   A 2  is ##STR203##  wherein R 29 , R 33 , R 34 , R 35  and R 36  are independently hydrogen or C 1-6  -alkyl optionally substituted with halogen, amino, hydroxyl or aryl;   R 33  and R 34 , R 33  and R 35  or R 34  and R 35  may optionally form --(CH 2 ) i  --Z--(CH 2 ) j  --, wherein i and j independently are 1 or 2 and Z is a valence bond;   n, m and q are independently 0, 1, 2, or 3;   o and p are independently 0 or 1;   M is --CR 37  ═CR 38  -;   R 37  and R 38  are independently hydrogen, or C 1-6  -alkyl optionally substituted with aryl;   G 2  is hydrogen or C 1-6  -alkyl;   R 1  is hydrogen, or C 1-6  -alkyl;   R 2  is hydrogen, --C(═O)--R 54  or C 1-6  -alkyl;   R 3  and R 4  may be taken together to form ═S, ═O;   L 1  is CR 57  ;   L 2  is CR 58  ;   R 57  and R 58  independently are hydrogen, C 1-6  -alkyl, optionally substituted with hydroxyl, halogen, C 1-6  -alkoxy, or aryl;   a and b independently are 0, 1, 2, or 3; or a pharmaceutically acceptable salt thereof.     
     
     
       2. A compound of formula I ##STR204## wherein A is A 2  ; G is G 2  ;   D is ##STR205##  wherein R 5 , R 6 , R 7 , R 8 , and R 9  independently are hydrogen, halogen, aryl, C 1-6  -alkyl or C 1-6  -alkoxy;   E is ##STR206##  wherein R 10  and R 11  independently are hydrogen, halogen, aryl, C 1-6  -alkyl, C 1-6  -alkoxy, --CONR 15  R 16 , --(CH 2 ) v  --NR 15  SO 2  R 17 , --(CH 2 ) v  --NR 15  COR 16 , --(CH 2 ) v  --OR 17 , --(CH 2 ) v  --OCOR 16 , --CH(R 15 )R 16 , --(CH 2 ) v  --NR 15  --CS--NR 16  R 18  or --(CH 2 ) v  --NR 15  --CO--NR 16  R 18 ,   X 4  is --C(R 22 )═ or --N═;   R 19  is hydrogen or C 1-6  -alkyl optionally substituted with aryl,   R 20 , R 21  and R 22  independently are hydrogen, --COOR 23 , --CONR 24  R 25 , --(CH 2 ) w  NR 24  R 25 , --(CH 2 ) w  OR 23 , --(CH 2 ) w  R 23  or halogen;   R 15  or, R 16 , independently are hydrogen or C 1-6  -alkyl optionally substituted with halogen, --N(R 26 )R 27 , hydroxyl, C 1-6  -alkoxy, C 1-6  -alkoxycarbonyl, C 1-6  -alkylcarbonyloxy or aryl,   R 17  is C 1-6  alkyl substituted with aryl;   R 18  is C 1-6  alkyl;   R 26  and R 27  are independently hydrogen or C 1-6  -alkyl;   v and w are independently 0, 1, 2 or 3;   A 2  is ##STR207##  wherein R 29 , R 33 , R 34 , R 35  and R 36  are independently hydrogen or C 1-6  -alkyl optionally substituted with halogen, amino, hydroxyl or aryl;   R 33  and R 34 , R 33  and R 35  or R 34  and R 35  may optionally form --(CH 2 ) i  --Z--(CH 2 ) j  --, wherein i and j independently are 1 or 2 and Z is a valence bond;   n, m and q are independently 0, 1, 2, or 3;   o and p are independently 0 or 1;   M is --CR 37  ═CR 38  --;   R 37  and R 38  are independently hydrogen, or C 1-6  -alkyl optionally substituted with aryl;   G 2  is hydrogen or C 1-6  -alkyl;   R 54  is hydrogen or C 1-6  -alkyl,   R 3  and R 4  may be taken together to form ═S, ═O;   L 1  is CR 57  ;   L 2  is CR 58  ;   R 57  and R 58  independently are hydrogen, C 1-6  -alkyl, optionally substituted with hydroxyl, halogen, C 1-6  -alkoxy, or aryl;   a and b independently are 0, 1, 2, or 3; or a pharmaceutically acceptable salt thereof.     
     
     
       3. The compound according to claim 1, wherein A is   R.sup.33 --NH--(CR.sup.34 R.sup.35).sub.p (CH.sub.2).sub.m --M--(CHR.sup.36).sub.o --(CH.sub.2).sub.n --     wherein   R 33  is hydrogen or C 1-6  alkyl optionally substituted with hydroxyl,   R 34  and R 35  are independently of each other C 1-6  alkyl,   R 36  is hydrogen,   M is --CR 37  ═CR 38 , wherein R 37  and R 38  are hydrogen, p is 1, m is 1, o is 0 or 1 and n is 0 or 1.   
     
     
       4. The compound according to any one of claims 1-3, wherein D is ##STR208## wherein R 5  and R 6  independently of each other are hydrogen or C 1-6  alkyl. 
     
     
       5. The compound according to any one of claims 1-4, wherein E is ##STR209## wherein R 10  and R 11  independently of each other are hydrogen or C 1-6  alkyl. 
     
     
       6. The compound according to any one of claims 1-5, wherein R 1  is hydrogen or C 1-6  alkyl. 
     
     
       7. The compound according to any one of claims 1-6, wherein R 2  is hydrogen, --C(═O)--R 54  or C 1-6  alkyl, wherein R 54  is C 1-6  alkyl. 
     
     
       8. The compound according to any one of claims 1-7, wherein R 3  and R 4  are taken together to form ═O. 
     
     
       9. The compound according to any one of claims 1-8, wherein a is 1. 
     
     
       10. The compound according to any one of claims 1-9, wherein b is 0 or 1. 
     
     
       11. The compound according to any one of claims 1-10, wherein L 1  is --CH--. 
     
     
       12. The compound according to any one of claims 1-11, wherein L 2  is --CH-- or >N--. 
     
     
       13. The compound according to claim 1, selected from the group consisting of (2E)-5-Amino-5-methyl-N-methyl-N-((1R)-1-(N-methyl-N-(2-(2-thienyl)ethyl)carbamoyl)-2-(2-naphthyl)ethyl)hex-2-enamide,   (2E)-5-Methyl-5-(methylamino)-N-methyl-N-((1R)-1-(N-methyl-N-(2-(2-thienyl)ethyl)carbamoyl)-2-(2-naphthyl)ethyl)hex-2-enamide,   (2R)-2-(N-(3-(1-Aminoethyl)benzoyl)-N-methylamino)-N-methyl-3-(2-naphthyl)-N-(2-(2-thienyl)ethyl)propionamide, and   (2E)-5-Amino-N-((1R)-2-(biphenyl-4-yl)-1-(N-methyl-N-(2-(2-thienyl)ethyl)carbamoyl)ethyl)-5-methyl-N-methylhex-2-enamide; or a pharmaceutically acceptable salt thereof.     
     
     
       14. A pharmaceutical composition comprising, as an active ingredient, a compound according to any one of the claims 1-13 or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or diluent. 
     
     
       15. The composition according to claim 14 in unit dosage form, comprising from about 10 to about 200 mg of the compound according to any one of the claims 1-13 or a pharmaceutically acceptable salt thereof. 
     
     
       16. A pharmaceutical composition according to any one of the claims 14-15 for oral, nasal, transdermal, pulmonal, or parenteral administration.